Multiparticulate controlled porosity osmotic

ABSTRACT

The instant invention is directed to a multiparticulate osmotic pump, for the controlled release of a pharmaceutically active agent to an environment of use, said pump comprising: 
     (I) a carrier medium which does not maintain its integrity in the environment of use; 
     (II) a multiple of tiny osmotic pump elements each consisting essentially of: 
     (A) a core comprises at least one pharmacologically active agent soluble in an external fluid, or a mixture of an agent having a limited solubility in the external fluid with an osmotically effective solute that is soluble in the fluid, which exhibit an osmotic pressure gradient across the wall against the external fluid surrounded by 
     (B) a rate controlling water insoluble wall, having a fluid permeability of 6.96×10 -18  to 6.96×10 14  cm 3  sec/g and a reflection coefficient of less than 0.5, prepared from: 
     (i) a polymer permeable to water but impermeable to solute and 
     (ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), of at least one pH insensitive pore forming additive dispersed throughout said wall.

This is a continuation-in-part of application Ser. No. 850,576, filedApr. 11, 1986 now abandoned, which is a continuation of application Ser.No. 689,540, filed Jan. 7, 1985now abandoned, which is acontinuation-in-part of application Ser. No. 622,808filed June 20, 1984,now abandoned.

BACKGROUND OF THE INVENTION

This invention concerns an osmotically activated system for dispensingpharmacologically active agent(s). The system comprises an inner corecompartment of osmotically active composition surrounded by an enclosingwall material. The core comprises pharmacologically active agent(s)soluble in an external fluid, or a mixture of agent(s) having a limitedsolubility in the external fluid with osmotically effective solute(s)that is/are soluble in the fluid, which exhibit an osmotic pressuregradient across the wall against the external fluid. The wallconstitutes a layer of controlled porosity that is substantiallypermeable to both the external fluid and the core composition. Agent isreleased from the system by fluid imbibition through the wall into theinner core compartment at a rate controlled by the wall composition anddimensions, producing a solution containing agent that is releasedthrough the wall at a controlled rate in response to fluid volume flux,dV/dt, resulting from the osmotic pressure gradient, and diffusive flux,(dM/dt)_(D), driven by the chemical potential gradient of the agentacross the wall. The total rate of agent release, (dM/dt)_(T), is givenby Equation 1 where C is the concentration ##EQU1## of the active agentin the dissolved core composition and remains constant when excess solidcore mass is present. For the special case where the core mass is pureactive agent, the dissolved concentration is equal to the acitve agentsolubility, S, in the fluid. In the present invention the volume fluxcontribution, (dV/dt)C, to the total rate is greater than the diffusivecontribution, (dM/dt)_(D), and forms the basis for the osmotic pumpaction of the device.

The object of this invention is to provide an osmotically actuatedsystem for controlled delivery of pharmacologically active agents tobiological receptor sites over a prolonged period of time.

The controlled porosity wall of the present invention is substantiallypermeable to both solute and external fluid. The wall is composed ofmaterials that maintain their physical and chemical integrity during thecontrolled dispensing of agent in mixture with materials that can beleached into the external fluid. The wall has programmable fluidtransmission and agent release rates which provide for controlledrelease of agent which is free from environmental influences includingpH and degree of external fluid agitation.

The wall may be composed of either insoluble, non-erodible materialsmixed with leachable additives, or bioerodible materials containingleachable additives. Bioerodible materials would be selected to bioerodeafter a predetermined period with bioerosion occurring subsequent to theperiod of agent release.

Another object of the invention is to provide an osmotic system that isreadily manufactureable to deliver a pre-determined dose of agent at aprogrammed rate from compositions of matter in the varied geometries andsizes of tablets, pellets, multi-particulates, and such related dosageforms as familiar to those skilled in the art for oral, buccal, vaginal,rectal, nasal, ocular, aural, parenteral and related routes ofadministration. Another object of the invention is to provide an osmoticsystem that delivers agent on an equivalent mass per unit surface areabasis.

The use of pore formers in substantially water impermeable polymers,such as polyvinyl chloride, is disclosed in J. Pharm. Sci. 72, 772-775and U.S. Pat. No. 4,244,941. These devices are not osmotic pumps. Thedevices release the core contents by simple diffusion through the poresin the coating.

U.S. Pat. No. 3,957,523 discloses a device which has pH sensitive poreformers in the wall.

U.S. Pat. Nos. 4,256,108; 4,160,452; 4,200,098 and 4,285,987 disclosedevices with pore formers in only one of at least two wall layers. Thesedevices contain a drilled hole for the release of the core contents.

A BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an embodiment of the osmotic pump element (1), having anosmotically active core composition (3) comprised of either pure agent(4) or a mixture of agents (4) and (5).

FIG. 2 is the release profile (statistical average of several pumps) ofthe pumps produced in Examples 1 through 3.

FIGS. 3, 4, 6, 7 and 9 through 16 are the release profiles of the pumpsproduced in Examples 4 through 15, respectively.

FIG. 5 is a plot of 1/(wall thickness) versus mean release rate of thepumps produced in Example 5.

FIG. 8 is a plot of release rate versus the net osmotic pressuredifference for the pumps produced in Example 7.

FIG. 17 is a scanning electron micrograph of a leached wall sample fromthe device described in Example 16, illustrating porosity and poresizes.

FIG. 18 shows embodiments of multiparticular osmotic pumps (18a) and(18b) in a solid carrier medium (7) and a hollow carrier medium (9).Both embodiments contain multiple pump elements (1) as detailed inFIG. 1. The embodiments can be distinguished by the solid matrix (6) ofembodiment (7) and the hollow spaces (8) of embodiment (9) which areformed by those areas of the carrier medium not occupied by the osmoticpump elements (1).

DESCRIPTION OF THE INVENTION

The instant invention is directed to a multiparticulate osmotic pump,for the controlled release of a pharmaceutically active agent to anenvironment of use, said pump comprising:

(I) a carrier medium which does not maintain its integrity in theenvironment of use;

(II) a multiple of tiny osmotic pump elements each consistingessentially of:

(A) a core comprises at least one pharmacologically active agent solublein an external fluid, or a mixture of a agent having a limitedsolubility in the external fluid with a osmotically effective solutethat is soluble in the fluid, which exhibit an osmotic pressure gradientacross the wall against the external fluid surrounded by

(B) a rate controlling water insoluble wall, having a fluid permeabilityof 6.96×10⁻¹⁸ to 6.96×10⁻¹⁴ cm³ sec/g and a reflection coefficient ofless than 0.5, prepared from:

(i) a polymer permeable to water but impermeable to solute and

(ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), ofat least one pH insensitive pore forming additive dispersed throughoutsaid wall.

The phrase "permeable to water but impermeable to solutes" means thewater permeates through the polymer preferably to solute, under apressure differential.

Referring to FIG. 1, each osmotic pump element is typically in the formof a coated tablet or shaped for rectal or vaginal applications, andcoated pellets, beads and multi-particulates having the essentialfeatures and elements of FIG. 1, of a size such that several suchdevices may be loaded into solid carrier media, such as a solublegelatin capsule or tablet matrix for oral administrations or suspendedin a suitable fluid carrier media for injection, oral administration orspraying. Whether solid or fluid, the carrier media become disrupted inthe environment of use, thereby freeing the osmotic pump elements torelease the active agent at a predetermined controlled rate.

The water insoluble, permeable wall (2) of controlled porosity may beapplied to osmotically active core composition masses (3) by spraycoating procedures. The wall is comprised of (a) polymeric material thatis insoluble in the fluids of the environment of intended use (usuallywater); (b) other added excipients that will dissolve in theenvironmental fluids and leach out of the wall. Referring to FIG. 17,the leached wall is a sponge-like structure composed of numerous openand closed cells that form a discontinuous interwoven network of voidspaces when viewed with a scanning electron microscope. This controlledporosity wall serves as both the water entry and core compositionsolution exit sites. The wall is permeable to both water and solutes,and as constituted in the environment of use has a small solutereflection coefficient, σ, and displays poor semipermeablecharacteristics when placed in a standard osmosis cell.

The specifications for the wall are summarized below and include:

    ______________________________________                                        1.  Fluid Permeability                                                                           6.96 × 10.sup.-18 to 6.96 ×                        of the wall    10.sup.-14 cm.sup.3 sec/g                                                     (equivalent to 10.sup.-5 to                                                   10.sup.-1 cm.sup.3 /mil/cm.sup.2 hr atm)                   2.  Reflection     Microporous coats to                                           Coefficient    have a reflection                                                             coefficient, σ, defined                                                 as:                                                                            ##STR1##                                                                     where σ is less than 1, usually                                         0 to 0.8.                                                  ______________________________________                                    

A specific embodiment of the present invention are those osmotic pumpswherein the reflection coefficient of the wall is less than 0.5.Exemplifying this embodiment are those osmotic pumps wherein thereflection coefficient of the wall is less than 0.1.

Additional, preferred specifications for the wall include:

    ______________________________________                                        1.      Plasticizer and                                                                             0 to 50, preferably 0.001                                       Flux Regulating                                                                             to 50, parts per 100 parts                                      Additives     wall material                                           2.      Surfactant    0 to 40, preferably .001                                        Additives     to 40, parts per 100 parts                                                    wall material                                           3.      Wall          1 to 1,000, preferably 20                                       Thickness     to 500, microns typically                                                     although thinner and                                                          thicker fall within the                                                       invention                                               4.      Microporous   5% to 95% pores between                                         Nature        10 angstroms and 100                                                          microns diameter                                        5.      Pore forming  0.1 to 60%, preferably 0.1                                      Additives     to 50%, by weight, based                                                      on the total weight of                                                        pore forming additive and                                                     polymer, pH insensitive                                                       pore forming additive,                                                        preferably:                                                                   (a) 0.1 to 50%, preferably                                                    0.1 to 40%, by weight                                                         solid additive                                                                (b) 0.1 to 40% by weight                                                      liquid additive                                                               But no more than 60% total                                                    pore formers.                                           ______________________________________                                    

The water insoluble wall of the instant invention must not be covered onits inner or outer surface by a layer of material that is impermeable todissolved solutes within the core during the period of pumpingoperation.

Any polymer permeable to water but impermeable to solutes as previouslydefined may be used. Examples include cellulose acetate having a degreeof substitution, D.S., meaning the average number of hydroxyl groups onthe anhydroglucose unit of the polymer replaced by a substituting group,up to 1 and acetyl content up to 21%; cellulose diacetate having a D.S.of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetatehaving a D.S. of 2 to 3 and an acetyl content of 35 and 44.8%; cellulosepropionate having an acetyl content of 1.5 to 7% and a propionyl contentof 2.5 to 3% and an average combined propionyl content of 39.2 to 45%and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate havinga D.S. of 1.8, an acetyl content of 13 to 15%, and a butyryl content of34 to 39%; cellulose acetate having an acetyl content of 2 to 99.5%, abutyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%;cellulose triaceylates having a D.S. of 2.9 to 3 such as cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate, cellulose triheptylate, cellulose tricaprylate, cellulosetrioctanoate, and cellulose tripropionate; cellulose diesters having alower degree of substitution and prepared by the hydrolysis of thecorresponding triester to yield cellulose diacylates having a D.S. of2.2 to 2.6 such as cellulose dicapyrlate and cellulose dipentanate; andesters prepared from acyl anhydrides or acyl acids in an esterificationreaction to yield esters containing different acyl groups attached tothe same cellulose polymer such as cellulose acetate valerate, celluloseacetate succinate, cellulose propionate succinate, cellulose acetateoctanoate, cellulose valerate palmitate, cellulose acetate palmitate andcellulose acetate heptanoate.

Additional polymers that can be used for the purpose of the inventioninclude cellulose acetate acetoacetate, cellulose acetate chloroacetate,cellulose acetate furoate, dimethoxyethyl cellulose acetate, celluloseacetate carboxymethoxypropionate, cellulose acetate benzoate, cellulosebutyrate naphthylate, cellulose acetate benzoate, methylcelluloseacetate methylcyanoethyl cellulose, cellulose acetate methoxyacetate,cellulose acetate ethoxyacetate, cellulose acetate dimethylsulfamate,ethylcellulose, ethylcellulose dimethylsulfamate, cellulose acetatep-toluene sulfonate, cellulose acetate methylsulfonate, celluloseacetate dipropylsulfamate, cellulose acetate butylsulfonate, celluloseacetate laurate, cellulose stearate, cellulose acetate methylcarbamate,agar acetate, amylose triacetate beta glucan acetate, beta glucantriacetate, acetaldehyde dimethyl acetate, cellulose acetate ethylcarbamate, cellulose acetate phthalate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, poly (vinyl methyl)ether copolymers, cellulose acetate with acetylated hydroxyethylcellulose hydroxylated ethylenevinylacetate, poly (ortho ester)s,polyacetals, semipermeable polyglycolic or polylactic acid andderivatives thereof, selectively permeable associated polyelectrolytes,polymers of acrylic and methacrylic acid and esters thereof, filmforming materials with a water sorption of one to fifty percent byweight at ambient temperatures with a presently preferred water sorptionof less than thirty percent, acylated polysaccharides, acylatedstarches, aromatic nitrogen containing polymeric materials that exhibitpermeability to aqueous fluids, membranes made from polymeric epoxides,copolymers of alkylene oxides and alkyl glycidyl ethers, polyurethanes,and the like. Admixtures of various polymers may also be used.

The polymers described are known to the art or they can be preparedaccording to the procedures in Encyclopedia of Polymer Science andTechnology, Vol. 3, pages 325 to 354, and 459 and 549, published byInterscience Publishers, Inc., New York, in Handbook of Common Polymersby Scott, J. R. and Roff, W. J., 1971, published by CRC Press,Cleveland, Ohio; and in U.S. Pat. Nos. 3,133,132; 3,173,876; 3,276,586;3,541,055; 3,541,006; and 3,546,142.

A controlled porosity wall can be generically described as having asponge-like appearance. The pores can be continuous pores that have anopening on both faces of a microporous lamina, pores interconnectedthrough tortuous paths of regular and irregular shapes including curved,curved-linear, randomly oriented continuous pores, hindered connectedpores and other porous paths discernible by microscopic examination.Generally, microporous lamina are defined by the pore size, the numberof pores, the tortuosity of the microporous path and the porosity whichrelates to the size and number of pores. The pore size of a microporouslamina is easily ascertained by measuring the observed pore diameter atthe surface of the material under the electron microscope as shown inFIG. 17. Generally, materials possessing from 5% to 95% pores and havinga pore size of from 10 angstroms to 100 microns can be used.

Any pH insensitive pore forming additives may be used in the instantinvention. The microporous wall may be formed in situ, by a pore-formerbeing removed by dissolving or leaching it to form the microporous wallduring the operation of the system. The pores may also be formed in thewall prior to operation of the system by gas formation within curingpolymer solutions which result in voids and pores in the final form ofthe wall. The pore-former can be a solid or a liquid. The term liquid,for this invention embraces semi-solids, and viscous fluids. Thepore-formers can be inorganic or organic. The pore-formers suitable forthe invention include pore-formers than can be extracted without anychemical change in the polymer. Solid additives include alkali metalsalts such as sodium chloride, sodium bromide, potassium chloride,potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate,sodium citrate, potassium nitrate and the like. The slkaline earth metalsalts such as calcium chloride, calcium nitrate, and the like. Thetransition metal salts such as ferric chloride, ferrous sulfate, zincsulfate, cupric chloride, and the like. Water may be used as thepore-former. The pore-formers include organic compounds such assaccharides. The saccharides include the sugars sucrose, glucose,fructose, mannose, galactose, aldohexose, altrose, talose, lactose,monosaccharides, disaccharides, and water soluble polysaccharides. Also,sorbitol, mannitol, organic aliphatic and aromatic ols, including diolsand polyols, as exemplified by polyhydric alcohols, poly(alkyleneglycols), polyglycols, alkylene glycols, poly(α-ω)alkylenediols estersor alkylene glycols poly vinylalcohol, poly vinyl pyrrolidone, and watersoluble polymeric materials. Pores may also be formed in the wall by thevolatilization of components in a polymer solution or by chemicalreactions in a polymer solution which evolves gases prior to applicationor during application of the solution to the core mass resulting in thecreation of polymer foams serving as the porous wall of the invention.The pore-formers are nontoxic, and on their removal channels are formedthat fill with fluid. The channels become a transport path for fluid. Ina preferred embodiment, the non-toxic pore-forming agents are selectedfrom the group consisting of inorganic and organic salts, carbohydrates,polyalkylene glycols, poly(α-ω) alkylenediols, esters of alkyleneglycols, and glycols, that are used in a biological environment.

The microporous materials can be made by etched nuclear tracking, bycooling a solution of flowable polymer below the freezing point withsubsequent evaporation of solvent to form pores, by gas formation in apolymer solution which upon curing results in pore formation, by cold orhot stretching at low or high temperatures until pores are formed, byleaching from a polymer a soluble component by an appropriate solvent,by ion exchange reaction, and by polyelectrolyte processes. Processesfor preparing microporous materials are described in Synthetic PolymerMembranes, by R. E. Kesting, Chapters 4 and 5, 1971, published by McGrawHill, Inc.; Chemical Reviews, Ultrafiltration, Vol. 18, pages 373 to455, 1934; Polymer Eng. and Sci., Vol. 11, No. 4, pages 284 to 288,1971; J. Appl. Poly. Sci., Vol. 15, pages 811 to 829, 1971; and in U.S.Pat. Nos. 3,565,259; 3,615,024; 3,751,536; 3,801,692; 3,852,224; and3,849,528.

It is generally desirable from a preparation standpoint to mix thepolymer in a solvent. Exemplary solvents suitable for manufacturing thewall of the osmotic device include inert inorganic and organic solventsthat do not adversely harm the core, wall, and the materials forming thefinal wall. The solvents broadly include members selected from the groupconsisting of aqueous solvents, alcohols, ketones, esters, ethers,aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatics,heterocyclic solvents and mixtures thereof. Typical solvents includeacetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butylalcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, ethyllactate, n-heptane, ethylene glycol monoethyl ether, ethylene glycolmonoethyl acetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon tetrachloride, nitroethane, nitropropane,tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane,cyclooctane, dimethylbromamide, benzene, toluene, naphtha, 1,4-dioxane,tetrahydrofuran, diglyme, water, and mixtures thereof such as acetoneand water, acetone and methanol, acetone and ethyl alcohol, methylenedichloride and methanol, and ethylene dichloride and methanol.Illustrative of mixed solvents are acetone-methanol (80:20),acetone-ethanol (90:10), methylene dichloridemethanol (80:20),nitroethane-ethanol (50:50), nitroethane-ethanol (80:20), ethylacetate-ethanol (80:20), ethylene dichloride-methanol (80:20),methylenedichloride-methanol (78:22), acetone-water (90:10),chloroform-ethanol (80:20), methylenedichloride-ethanol (79:21),methylene chloridemethanol-water (75:22:3), carbontetrachloridemethanol(70:30), expressed as (weight:weight), and the like.

Exemplary plasticizers suitable for the present purpose includeplasticizers that lower the temperature of the second-order phasetransition of the wall or the elastic modulus thereof; and also increasethe workability of the wall, its flexibility and its permeability tofluid. Plasticizers operable for the present purpose include both cyclicplasticizers and acyclic plasticizers. Typical plasticizers are thoseselected from the group consisting of phthalates, phosphates, citrates,adipates, tartrates, sebacates, succinates, glycolates, glycerolates,benzoates, myristates, sulfonamides, and halogenated phenyls. Generally,from 0.001 to 50 parts of a plasticizer or a mixture of plasticizers areincorporated into 100 parts of wall forming material.

Exemplary plasticizers include dialkyl phthalates, dicycloalkylphthalates, diaryl phthalates and mixed alkylaryl as represented bydimethyl phthalate, dipropyl phthalate, di-(2-ethylhexyl)-phthalate,di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate; alkyland aryl phosphates such as tributyl phosphate, trioctyl phosphate,tricresyl phosphate and triphenyl phosphate; alkyl citrate and citrateesters such as tributyl citrate, triethyl citrate, and acetyl triethylcitrate; alkyl adipates such as dioctyl adipate, diethyl adipate anddi-(2-methyoxyethyl)adipate; dialkyl tartrates sucha s diethyl tartrateand dibutyl tartrate; alkyl sebacates such as diethyl sebacate, dipropylsebacate and dinonyl sebacate; alkyl succinates such as diethylsuccinate and dibutyl succinate; alkyl glycolates, alkyl glycerolates,glycol esters and glycerol esters such as glycerol diacetate, glyceroltyriacetate, glycerol monolactate diacetate, methyl phthalyl ethylglycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate,ethylene glycol dibutyrate, triethylene glycol diacetate, triethyleneglycol dibutyrate and triethylene glycol dipropionate. Otherplasticizers include camphor, N-ethyl-(o- and p-toluene) sulfonamide,chlorinated biphenyl, benzophenone, N-cyclohexyl-p-toluene sulfonamide,and substituted epoxides.

Suitable plasticizers can be selected for blending with the wall formingmaterials by selecting plasticizers that have a high degree of solventpower for the materials, are compatible with the materials over both theprocessing and use temperature range, exhibit permanence as seen bytheir strong tendency to remain in the plasticized wall, impartflexibility to the material and are non-toxic to animals, humans,avians, fishes and reptiles. Procedures for selecting a plasticizerhaving the described characteristics are disclosed in the Encyclopediaof Polymer Science and Technology, Vol. 10, pages 228 to 306, 1969,published by John Wiley & Sons, Inc. Also, a detailed descriptionpertaining to the measurement of plasticizer properties includingsolvent parameters and compatibility such as the Hildebrand solubilityparameter δ the Flory-Huggins interaction parameter χ, and thecohesive-energy density, CED, parameters are disclosed in Plasticizationand Plasticizer Processes, Advances in Chemistry Series 48, Chapter 1,pages 1 to 26, 1965, published by the American Chemical Society. Theamount of plasticizer added generally is an amount sufficient to producethe desired wall and it will vary according to the plasticizer and thematerials. Usually about 0.001 part up to 50 parts of plasticizer can beused for 100 parts of wall material.

The expressions "flux regulator agent", "flux enhancing agent" and "fluxdecreasing agent" as used herein mean a compound that when added to awall forming material assists in regulating the fluid permeability offlux through the wall. The agent can be preselected to increase ordecrease the liquid flux. Agents that produce a marked increase inpermeability to fluid such as water, are often essentially hydrophilic,while those that produce a marked decrease to fluids such as water, areessentially hydrophobic. The flux regulators in some embodiments alsocan increase the flexibility and porosity of the lumina. Examples offlux regulators include polyhydric alcohols and derivatives thereof,such as polyalkylene glycols of the formula H-(O-alkylene)_(n) -OHwherein the bivalent alkylene radical is straight or branched chain andhas from 1 to 10 carbon atoms and n is 1 to 500 or higher. Typicalglycols include polyethylene glycols 300, 400, 600, 1500, 1540, 4000 and6000 of the formula H-(OCH₂ CH₂)_(n) -OH wherein n is respectively 5 to5.7, 8.2 to 9.1, 12.5 to 13.9, 29 to 36, 29.8 to 37, 68 to 84, and 158to 204. Other polyglycols include the low molecular weight glycols suchas polypropylene, polybutylene and polyamylene.

Additional fux regulators include poly (α,ω)alkylendiols wherein thealkylene is straight or branched chain of from 2 to 10 carbon atoms suchas poly(1,3)propanediol, poly(1,4)butanediol, poly(1,5)pentanediol andpoly(1,6)hexanediol. The diols also include aliphatic diols of theformula HOC_(n) H_(2n) OH wherein n is from 2 to 10 and diols areoptionally bonded to a non-terminal carbon atom such as 1,3-butyleneglycol, 1,4-pentamethylene glycol, 1,5-hexamethylene glycol and1,8-decamethylene glycol; and alkylenetriols having 3 to 6 carbon atomssuch as glycerine, 1,2,3-butanetriol, 1,2,3-pentanetriol,1,2,4-hexanetriol and 1,3,6-hexanetriol.

Other flux regulators include esters and polyesters of alkylene glycolsof the formula HO-(alkylene-O)_(n) -H wherein the divalent alkyleneradical includes the straight chain groups and the isomeric formsthereof having from 2 to 6 carbons and n is 1 to 14. The esters andpolyesters are formed by reacting the glycol with either a monobasic ordibasic acid. Exemplary flux regulators are ethylene glycoldipropionate, ethylene glycol butyrate, ethylene glycol diacetae,triethylene glycol diacetate, butylene glycol dipropionate, polyester ofethylene glycol with succinic acid, polyester of diethylene glycol withmaleic acid, and polyester of triethylene glycol with adipic acid.

The amount of flux regulator added to a material generally is an amountsufficient to produce the desired permeability, and it will varyaccording to the lamina forming material and the flux regulator used tomodulate the permeability. Usually from 0.001 parts up to 50 parts, orhigher of flux regulator can be used to achieve the desired results.

Surfactants useful for the present purpose are those surfactants, whenadded to a wall forming material and otehr materials, aid in producingan integral composite that is useful for making the operative wall of adevice. The surfactants act by regulating the surface energy ofmaterials to improve their blending into the composite. This lattermaterial is used for manufacturing devices that maintain their integrityin the environment of use during the agent release period. Generally,the surfactants are amphipathic molecules comprised of a hydrophobicpart and a hydrophilic part. The surfactants can be anionic, cationic,nonionic or amphoteric, and they include anionics such as sulfatedesters, amides, alcohols, ethers and carboxylic acids; sulfonatedaromatic hydrocarbons, aliphatic hydrocarbons, esters and ethers;acylated amino acids and peptides; and metal alkyl phosphates; cationicsurfactants such as primary, secondary, tertiary and quaternaryalkylammonium salts; acylated polyamines; and salts of heterocyclicamines, arylammonium surfactants such as esters of polyhydric alcohols;alkoxylated amines; polyoxyalkylene; esters and ethers ofpolyoxyalkylene glycols; alkanolamine fatty acid condensates; tertiaryacetylamic glycols; and dialkyl polyoxyalkylene phosphates; andampholytics such as betamines; and amino acids.

Typical surfactants include polyoxyethylenated glycerol ricinoleate;polyoxyethylenated castor oil having from 9 to 52 moles of ethyleneoxide; glycerol mannitan laurate, and glycerol (sorbitan oleates,stearates or laurates); polyoxyethylenated sorbitan laurate, palmitate,stearate, oleate or hexaolate having from 5 to 20 moles of ethyleneoxide; mono-, di- and poly-ethylene glycol stearates, laurates, oleates,myristates, behenates or ricinoleates; propylene glycol carboxylic acidesters; sorbitan laurate, palmitate, oleate, and stearate;polyoxyethylenated octyl, nonyl, decyl, and dodecylphenols having 1 to100 moles of ethylene oxide; polyoxyethylenated nonyl, lauryl, decyl,cetyl, oleyl and stearyl alcohols having from 3 to 50 moles of ethyleneoxide; polyoxypropylene glycols having from 3 to 300 moles of ethyleneoxide; sodium salt of sulfated propyl oleate; sodiumdi-(heptyl)sulfosuccinate; potassium xylenesulfonate; 1:1 myristic aciddiethanolamide; N-coco-β-aminopropionic acid;bis-(2-hydroxyethyl)-tallowamine oxide;(diisobutyl-phenoxyethoxyethyl)dimethylbenzylammonium halide;N,N'-polyoxypropylenated ethylenediamine having a molecular weight from500 to 3000; tetra-alkylammonium salts with up to 26 carbon atoms in thecation; sodium or potassium salt of polypeptide cocoanut, oleic orundecylenic acid condensate; metal salts of N-acylated short chainaminosulfonic acids, soybean phosphatides; and sulfobetaine.

Suitable surfactants can be selected from the above and from othersurfactants for blending with wall forming materials by using thesurfactant's hydrophile-lipophile balance number, HLB. This numberrepresents the proportion between the weight percentages of hydrophilicand lipophilic groups in a dispersant. In use, the number indicates thebehavior of the surfactant, that is, the higher the number the morehydrophilic the surfactant and the lower the number the more lipophilicthe surfactant. The required HLB number for blending wall formingmaterials is determined by selecting a surfactant with a known number,blending it with the materials and observing the results. A homogeneouscomposite is formed with the correct number, while a heterogeneousmixture indicates a different number is needed. This new number can beselected by using the prior number as a guide. The HLB number is knownto the art for many surfactants, and they can be experimentallydetermined according to the procedure in J. Soc. Cosmetic Chem., Vol. 1,pages 311 to 326, 1949, or it can be calculated by using the procedurein J. Soc. Cosmetic Chem., Vol. 5, pages 249 to 256, 1954, and in Am.Perfumer Essent. Oil Rev., Vol 65, pages 26 to 29, 1955. Typical HLBnumbers are set forth in Table 1. Generally a number of 10 or lessindicates lipophilic behavior and 10 or more indicates hydrophilicbehavior. Also, HLB numbers are algebraically additive. Thus, by using alow number with a high number, blends of surfactants can be preparedhaving numbers intermediate between the two numbers. The amount ofsurfactant needed is an amount that when blended with wall formingmaterials will form the desired wall composite, and it will varyaccording to the particular surfactant and materials that are blended toform the wall. Generally, the amount of surfactant will range from about0.001 part up to 40 parts for 100 parts of wall.

                  TABLE 1                                                         ______________________________________                                        SURFACTANT            HLB NUMBER                                              ______________________________________                                        Sorbitan trioleate    1.8                                                     Polyoxyethylene sorbitol beeswax                                                                    2.0                                                     Sorbitan tristearate  2.1                                                     Poloxyethylene sorbitol hexastearate                                                                2.6                                                     Ethylene glycol fatty acid ester                                                                    2.7                                                     Propylene glycol fatty acid ester                                                                   3.4                                                     Propylene glycol monostearate                                                                       3.4                                                     Ethylene glycol fatty acid ester                                                                    3.6                                                     Glycerol monostearate 3.8                                                     Sorbitan monooleate   4.3                                                     Propylene glycol monolaurate                                                                        4.5                                                     Diethylene glycol fatty acid ester                                                                  5.0                                                     Sorbitan monopalmitate                                                                              6.7                                                     Polyoxyethylene dioleate                                                                            7.5                                                     Polyoxypropylene mannitol dioleate                                                                  8.0                                                     Sorbitan monolaurate  8.6                                                     Polyoxyethylene lauryl ether                                                                        9.5                                                     Polyoxyethylene sorbitan monolaurate                                                                10.0                                                    Polyoxyethylene lanolin derivative                                                                  11.0                                                    Polyoxyethylene glycol 400 monooleate                                                               11.4                                                    Triethanolamine oleate                                                                              12.0                                                    Polyoxyethylene nonyl phenyl                                                                        13.0                                                    Polyoxyethylene sorbitan monolaurate                                                                13.3                                                    Polyoxyethylene sorbitol lanolin                                                                    14.0                                                    Polyoxyethylene stearyl alcohol                                                                     15.3                                                    Polyoxyethylene 20 cetyl ether                                                                      15.7                                                    Polyoxyethylene 40 stearate                                                                         16.9                                                    Polyoxyethylene monostearate                                                                        17.9                                                    Sodium oleate         18.0                                                    Potassium oleate      20.0                                                    ______________________________________                                    

The osmotically active core composition mass (3) of FIG. 1, is typicallyin the form of a solid conventional tablet, pellet, or multiparticulate.The core is completely encased by the controlled porosity wall (2). Thecore can be comprised of either a pure agent (4) or a mixture of agents(4, 5, etc.) combined to give the desired manufacturing and ultimateagent(s) delivery characteristics. The number of agents that may becombined to make the core is substantially without an upper limit withthe lower limit equalling one component.

The preferred specifications for the core are summarized below andinclude:

    ______________________________________                                        1.      Core Loading  0.05 nanograms to 5 grams                                       (size)        or more (includes dosage                                                      forms for humans and                                                          animals)                                                2.      Osmotic       8 to 500 atmospheres,                                           pressure      typically, with commonly                                        developed     encountered water soluble                                       by a solution drugs and excipients;                                           of the core   however osmotic pressures                                                     greater than zero are                                                         within guidelines                                       3.      Core solubility                                                                             to get continuous, uniform                                                    release (zero-order                                                           kinetics) of 90% or                                                           greater of the initially                                                      loaded core mass, the                                                         ratio of the core mass                                                        solubility, S, to the                                                         core mass density, ρ,                                                     that is S/ρ, must be                                                      0.1 or lower. Typically                                                       this occurs when 10% of                                                       the initially loaded core                                                     mass saturates a volume                                                       of external fluid equal                                                       to the total volume of                                                        the initial core mass.                                  ______________________________________                                    

S/ρ ratios greater than 0.1 fall within the workings of the inventionand result in lower percentages of initial core mass delivered underzero-order kinetics. S/ρ can be selected to give acceptable combinedcharacteristics of stability, release rate, and manufacturability.

In cases where the active agent has the desired solubility, osmoticpressure, density, stability, and manufacturability characteristics,there is no critical upper limit as to the amount that can beincorporated into a core mass and typically will follow the core loading(size) specification 1. The lower limit ratio of agent to excipient isdictated by the desired osmotic activity of the core composition, thedesired time span of release, and the pharmacological activity of theactive agent. Generally the core will contain 0.01% to 90% by weight orhigher, of an active agent in mixture with another solute(s).Representative of compositions of matter that can be released from thedevice and can function as a solute are, without limitation, thosecompositions soluble in fluids inside the core compartment as described.The solubilized constituents create a water activity gradient across thewall, (2), of FIG. 1, resulting in osmotically actuated fluid movementconstituting the osmotic pump action of the invention.

The expression "active agent" as used herein broadly includes anycompound, or mixture thereof, that can be delivered from the system toproduce a beneficial result. The agent can be soluble in fluid thatenters the reservoir and functions as an osmotically effective solute orit can have limited solubility in the fluid and be mixed with anosmotically effective compound soluble in fluid that is delivered fromthe system. The active agent includes pesticides, herbicides,germicides, biocides, algicides, rodenticides, fungicides, insecticides,antioxidants, plant growth promoters, plant growth inhibitors,preservatives, disinfectants, sterilization agents, catalysts, chemicalreactants, fermentation agents, foods, food supplements, nutrients,cosmetics, drugs, vitamins, sex sterilants, fertility inhibitors,fertility promoters, air purifiers, microorganism attentuators, andother agents that benefit that environment of use.

In the specification and the accompanying claims, the term "drug"includes any physiologically or pharmacologically active substances thatproduce a localized or systemic effect or effects in animals, which termincludes mammals, humans and primates. The term also includes domestichousehold, sport or farm animals such as sheep, goats, cattle horses andpigs, for administering to laboratory animals such as mice, rats andguinea pigs, and to fishes, to avians, to reptiles and zoo animals. Theterm "physiologically" as used herein denotes the administration of drugto produce normal levels and functions. The term "pharmacologically"denotes variations in response to amounts of drug includingtherapeutics. Stedman's Medical Dictionary, 1966, published by Williams& Wilkins, Baltimore, Md. The phrase drug formulation as used hereinmeans the drug is in the compartment by itself, or the drug is in thecompartment mixed with an osmotic solute, binder, dye, mixtures thereof,and the like. The active drug that can be delivered includes inorganicand organic compounds without limitation, including drugs that act onthe peripheral nerves, adrenergic receptors, cholinergic receptors,nervous system, skeletal muscles, cardiovascular, smooth muscles, bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, immunological system, reproductivesystem, skeletal system, autocoid systems, alimentary and excretorysystems, inhibitory of autocoids and histamine systems, those materialsthat act on the central nervous system such as hypnotics and sedatives,including pentobarbital sodium, phenobarbital, secobarbital, thiopentaland mixtures thereof; heterocyclic hypnotics such as dioxopiperidinesand glutarimides; hypnotics and sedatives such as amides and ureas,exemplified by diethylisovaleramide and α-bromoisovaleryl urea; hypnoticand sedative urethanes and disulfanes; psychic energizers such asisocoboxazid, nialamide, phenelzine, imipramine, amitryptylinehydrochloride, tranylcypromine and pargylene; and protryptylinehydrochloride, tranquilizers such as chloropromazine, promazine,fluphenzaine, reserpine, deserpidine, meprobamate, and benzodiazepinessuch as chlordiazepoxide; anticonvulsants such as primidone, enitabas,diphenylhydantion, ethyltion, pheneturide and ethosuximide; musclerelaxants and antiparkinson agents such as mephenesin, methocarbomal,cyclobenzaprine trihexylphenidyl, levodopa/carbidopa, and biperiden;antihypertensives such as α-methyldopa andL-β-3-4-dihydroxyphenylalanine, and pivaloyloxyethyl ester ofα-methyldopa hydrochloride dihydrate; analgesics such as morphine,codeine, meperidine, nalorphine; antipyretics and anti-inflammatoryagents such as aspirin, indomethacin, sodium indomethacin trihydratesalicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal,diclofenac, indoprofen and sodium salicyl-amide; local anesthetics suchas procaine, lidocaine, maepaine, piperocaine, tetracaine and dibucane;antispasmodics and muscle contractants such as atropine, scopolamine,methscopolamine, oxyphenonium, papaverine; prostaglandins such as PGE₁,PGE₂, PGF₁α, PGF₂α and PGA; antimicrobials and antiparasitic agents suchas penicillin, tetracycline, oxytetracycline, chloro-tetracycline,chloramphenicol, thiabendazole, ivermectin, and sulfonamides;antimalarials such as 4-aminoquinolines, 8-aminoquinolines andpyrimethamine; hormonal agents such as dexamethasone prednisolone,cortisone, cortisol and triamcinolone; androgenic steroids such asmethyltestosterone, and fluoxmesterone; estrogenic steroids such as17β-estradiol, α-estradiol, estriol, α-estradiol 3-benzoate, and17-ethynyl estradiol-3-methyl ether; progestational steroids such asprogesterone, 19-nor-pregn-4-ene-3,20-dione,17-hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one,17α-ethynyl17-hydroxy-5(10)-estren-3-one, and 9β,10α-pregna-4,6-diene-3,20-dione; sympathomimetic drugs such asepinephrine, phenylpropoudamine hydrochloride, amphetamine, ephedrineand norepinephrine; hypotensive drugs such as hydralazine;cardiovascular drugs such as procainamide, procainamide hydrochloride,amyl nitrite, nitroglycerin, dipyredamole, sodium nitrate and mannitolnitrate; diuretics such as chlorathiozide, acetazolamide, methazolamide,hydrochlorothiazide, amiloride hydrochloride and flumethiazide,ethacrynic acid, furosemide; antiparasitics such as bephenium,hydroxynaphthoate, dichlorophen and dapsone; and neoplastics such asmechlorethamine, uracil mustard, 5-fluorouracil, 6-thioguanine andprocarbazine; β-blockers such as pindolol, propranolol, practolol,metoprolol, oxprenolol, timolol, timolol maleate, atenolol, alprenolol,and acebutolol; hypoglycemic drugs such as insulin, isophane insulin,protamine zinc insulin suspension, globin zinc insulin, extended insulinzinc suspension toblutamide, acetohexamide, tolazamide andchlorpropamide; antiulcer drugs such as cimetidine; nutritional agentssuch as ascorbic acid, niacin, nicotinamide, folic acid, choline,biotin, pantothenic acid, and vitamin B₁₂ ; essential amino acids;essential fats; eye drugs such as timolol, timolomaleate, pilocarpine,pilocarpine salts such as pilocarpine nitriate, pilocarpinehydrochloride, dichlorphenamide, atropine, atropine sulfate, scopolamineand eserine salicylate; histamine receptor antagonists such ascimetidine; and electrolytes such as calcium gluconate, calcium lactate,potassium chloride, potassium sulfate, sodium chloride, potassiumfluoride, sodium fluoride, ferrous lactate, ferrous gluconate, ferroussulfate, ferrous fumurate and sodium lactate; and drugs that act onα-adrenergic receptors such as clonidine hydrochloride.

Additional preferred drugs include quinoline and naphthyridinecarboxylic acids and related compounds, such as1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid; 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylicacid; 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylicacid;8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid;9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinoxolizine-2-carboxylicacid; 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylicacid;1-ethyl-1,4-dihydro-4-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylicacid;9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid;1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylicacid;1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylicacid; 1-cyclopropane-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid;1-methylamino-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-ipiperazinyl)-3-quinolinecarboxylicacid;1-(4-fluoro-1-phenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid;1-(4-fluoro-1-phenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinolinecarboxylicacid;1-(4-fluoro-1-phenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylicacid; and1-ethyl-6-fluoro-1,4-Dihydro-4-oxo-7-(3-ethylaminomethyl-1-pyrrolidinyl)-8-fluoro-3-quinolinecarboxylicacid.

Additional preferred drugs include drugs which affect the respiratorytract such as budesonide, enprofylline, tranilast, albuterol,theophylline, amoniphylline, brompheniramine, chlorpheniramine,promethazine, diphenhydramine, azatadine, cyproheptadine, terbutaline,metaproterenol, and isoproterenol; drugs which are antidepressants suchas amiflamine, alaproclate, doxepin, trazedone, maprotiline, zimelidine,fluvoxamine; antipsychotic drugs such as haloperidol, thioridazine,trifluoperazine, MK-0212, and remoxipride; sedative hypnotic andantianxiety drugs such as triazolam, temazepam, chlorazeptate,alprazolam, diazepam, fluorazepam, lorazepam, oxazepam, hydroxyzine,prazepam, meprobamate, butalbital, and chlorzoxazone; antiparkinsondrugs such as benztropine and L-647,339; hormonal and steroidal drugssuch as conjugated estrogens, diethylstilbesterol, hydroxy progesterone,medroxy progestrone, norethindrone, betamethasone, methylprednisolone,prednisone, thyroid hormone, levothyroxine and MK-0621; antihypertensiveand cardiovascular drugs such as isosorbide dinitrate, digoxin, nadolol,disopyramide, nifedipine, quinidine, lidocaine, diltiazam, verapamil,prazosin, captopril, enalapril, lisinopril, metyrosine, felodipine,tocainide, mexiletine, mecamylamine, and metyrosine; diuretic drugs suchas spironolactone, chlorthalidone, metolazone, triamterene,methyclothiazide, and indacrinone; antiinflammatory drugs such asibuprofen, phenylbutazone, tolmetin, piroxicam, melclofenamate,auranofin, flurbiprofen and penicillamine; analgesic drugs such asacetaminophen, oxycodone, hydrocodone, and propoxyphene; antiinfectivedrugs such as cefoxitin, cefazolin, cefotaxime, cephalexin, nicarbazin,amprolium, ampicillin, amoxicillin, cefaclor, erythromycin,nitrofurantoin, minocyline, doxycycline, cefadroxil, miconazoleclotrimazole, phenazopyridine, clorsulon, fludalanine, pentizidone,cilastin, phosphonomycin, imipenem, arprinocid, and foscarnet;gastrointestinal drugs such as bethanechol, clidinium, dicyclomine,meclizine, prochlorperizine, trimethobenzamide, loperamide, ranitidine,diphenoxylate, famotidine, metoclopramide and omeprazole; anticoagulantdrugs such as warfarin, phenindione, and anisindione; and other drugssuch as trientine, cambendazole, ronidazole, rafoxinide, dactinomycin,asparaginase, nalorphine, rifamycin, carbamezepine, metaraminolbitartrate, allopurinol, probenecid, diethylpropion, dihydrogenatedergot alkaloids, nystatin, pentazocine, phenylpropanolamine,phenylephrine, pseudoephedrine, trimethoprim and mevinolin.

The above list of drugs is not meant to be exhaustive. Many other drugswill certainly work in the osmotic pump of the instant invention.

Examples of beneficial drugs are disclosed in Remington's PharmaceuticalSciences, 16th Ed., 1980, published by Mack Publishing Co., Easton, Pa.;and in The Pharmacological Basis of Therapeutics, by Goodman and Gilman,6th Ed., 1980, published by The MacMillian Company, London.

The drug can be in various forms, such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as hydrochlorides,hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrite,borate, acetate, maleate, tartrate, oleate, and salicylate. For aciddrugs, salts of metals, amines or organic cations, for examplequaternary ammonium can be used. Derivatives of drugs such as esters,ethers and amides which have solubility characteristics suitable for useherein can be used alone or mixed with other drugs. Also, a drug that iswater insoluble can be used in a form that is a water soluble derivativethereof to effectively serve as a solute, and on its release from thedevice, is converted by enzymes, hydrolyzed by body pH or othermetabolic processes to the original form, or to a biologically activeform. The agent can be in the reservoir as a solution, dispersion,paste, cream, particle, granule, emulsion, suspension or powder. Also,the agent can be mixed with a binder, dispersant, emulsifier or wettingagent and dyes.

The amount of active agent or active agent admixed with otherosmotically active solutes present in the device is initially in excessof the amount that can be dissolved in the fluid that enters thereservoir. Under this physical state when the agent is in excess, thedevice will osmotically operate to give a substantially constant rate ofrelease. The rate of agent release pattern can also be varied by havingdifferent amounts of agent in the reservoir to form solutions containingdifferent concentrations of agent for delivery from the device.Generally, the device can house from 0.05 ng to 5 grams or more, withindividual devices containing, for example, 25 ng, 1 mg, 5 mg, 250 mg,500 mg, 1.5 g and the like.

Mixtures of drug agent(s) with other osmotically effective compounds maybe used to attract fluid into the device producing a solution tocompound which is delivered from the device concomitantly transportingdrug agent to the exterior of the device. Examples include magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate,potassium chloride, calcium bicarbonate, sodium sulfate, calciumsulfate, potassium acid phosphate, calcium lactate, d-mannitol, urea,inositol, sorbitol, magnesium succinate, tartaric acid, carbohydratessuch as raffinose, sucrose, glucose, α-d-lactose monohydrate, andmixtures thereof. The compound is initially present in excess and it canbe in any physical form such as particle, crystal, pellet, tablet,strip, film or granule. The osmotic pressure of saturated solutions ofvarious osmotically effective compounds and for mixtures of compounds at37° C., in water, is listed in Table 2. In the table, the osmoticpressure π, is in atmospheres, atm. The osmotic pressure is measured ina commercially available osmometer that measures the vapor pressuredifference between pure water and the solution to be analyzed, andaccording to standard thermodynamic principles, the vapor pressure ratiois converted into osmotic pressure difference. In Table 2, osmoticpressures of from 20 atm to 500 atm are set forth; of course, theinvention includes the use of lower osmotic pressures from greater thanzero, and higher osmotic pressures than those set forth by way ofexample in Table 2. For example, in the gastrointestinal tract, theosmotic pressure gradient across the wall in the compartment will befrom greater than 0 up to 500 atm per membrane thickness. That is, theosmotic pressure in the compartment will be typically in excess of 8 atmup to 500 atm.

                  TABLE 2                                                         ______________________________________                                                             OSMOTIC PRESSURE                                         COMPOUND OR MIXTURE  (atm)                                                    ______________________________________                                        Lactose-Fructose     500                                                      Dextrose-Fructose    450                                                      Sucrose-Fructose     430                                                      Mannitol-Fructose    415                                                      Sodium Chloride      356                                                      Fructose             335                                                      Lactose-Sucrose      250                                                      Potassium Chloride   245                                                      Lactose-Dextrose     225                                                      Mannitol-Dextrose    225                                                      Dextrose-Sucrose     190                                                      Mannitol-Sucrose     170                                                      Sucrose              150                                                      Mannitol-Lactose     130                                                      Dextrose             82                                                       Potassium Sulfate    39                                                       Mannitol             38                                                       Sodium Phosphate Tribasic.12H.sub.2 O                                                              36                                                       Sodium Phosphate Dibasic.7H.sub.2 O                                                                31                                                       Sodium Phosphate Dibasic.12H.sub.2 O                                                               31                                                       Sodium Phosphate Dibasic Anhydrous                                                                 29                                                       Sodium Phosphate Monobasic.H.sub.2 O                                                               28                                                       ______________________________________                                    

The resulting device will have a water permeability driven by asaturated solution of the active agent, or mixtures of active agentswith other osmotically active solutes, at the temperature of use, of0.01 ml per cm² of surface area per day to 10 ml per cm² of surface areaper hour.

EXAMPLES 1 to 13 Performance of Individual Osmotic Pump Elements EXAMPLE1

A plurality of osmotic systems for the osmotically controlled release ofthe beneficial drug potassium chloride were made as follows: First, 650mg aliquots of commercially-available reagent grade potassium chlolride(active agent) were compressed to a hardness of 15 Kg by standardcompression techniques in a Stokes tableting machine fitted with a 3/8inch extra deep concave punch. A total of 700 g of such tablets wereprepared as osmotic core composition masses of the invention. Next, 36 gof Eastman cellulose acetate 398-10 (polymer) were added to methylenechloride (solvent), with subsequent addition of methanol (solvent) withhigh speed mechanical stirring to complete the dissolution of thepolymer. To this was added 7.9 g of polyethylene glycol 400(plasticizer, liquid pore forming additive and flux regulator). To thissolution was added in dropwise fashion with stirring a second solutionof water and methanol (solvent) containing 18 g of dissolved sorbitol(solid pore forming additive), to constitute the solution utilized toform the controlled porosity wall of the invention. The final solutioncontained approximately 2%, by weight, polymer in a solvent system ofmethylene chloride, methanol, and water in the approximate weight ratioof 15:10:1. The fluid permeability of the wall was 2.28×10⁻¹⁵ cm³ sec/gand its reflection coefficient was measured at 8.66×10⁻⁴. Next, 700 g ofthe potassium chloride osmotic core tablets was charged into acommercial Uni-Glatt fluidized bed machine wherein the wall formingsolution was applied to the cores until a thickness of 0.016 cm wasattained. The finished osmotic systems were dried in an oven at 50° C.to facilitate removal of residual solvents.

Finally, the potassium chloride release from these osmotic systems intodistilled water was monitored conductiometrically at 37° C. in acommercial Applied Analytical standard dissolution apparatus providing100 rpm stirring. The release profile is depicted in FIG. 2 labelled asMMP-50 (modified microporous, sorbitol 50% of polymer wt) and was foundto be continuous at a mean rate of 139 mg per hours for a prolongedperiod of approximately 4 hours. Since the solute is passing through thewall, it has a reflection coefficient substantially less than 1 and wasdetermined to be less than 0.1. The amount of potassium chloridereleased with zero-order kinetics was consistent with the theoreticallyanticipated amount which was calculated with Equation 1 to be 82.7% ofthe initial KCl loaded into the core mass ##EQU2## where M_(z) is theamount released in zero-order fashion, M_(t) is the initial KCl load, Sis the KCl solubility (343 g/ml), and ρ is the density of solid KCl (2g/cm³).

EXAMPLE 2

A plurality of osmotic systems were manufactured according to theprocedure of Example 1, wherein the conditions were as described exceptthat the sorbitol content of the wall forming solution was 9 g.Potassium chloride release from these systems was monitored according tothe procedure of Example 1. The release profile is depicted in FIG. 2labelled as MMP-25 and was found to be continuous for a prolonged periodat a mean rate of 120 mg per hour for approximately 5 hours. The fluidpermeability of the wall was 1.69×10⁻¹⁵ cm³ sec/g and the reflectioncoefficient of the wall was less than 0.1.

EXAMPLE 3

A plurality of osmotic systems were manufactured according to theprocedure of Example 1, wherein the conditions were as described exceptthat the sorbitol content of the wall forming solution was 3.6 g.Potassium chloride release from these systems was monitored according tothe procedure of Example 1. The release profile is depicted in FIG. 2labelled as MMP-10 and was found to be continuous for a prolonged periodat a mean rate of 80 mg per hour for approximately 7.5 hours. The fluidpermeability of the wall was 0.81×10⁻¹⁵ cm³ sec/g and the reflectioncoefficient of the wall was less than 0.1.

EXAMPLE 4

A plurality of osmotic systems were manufactured according to therocedures of Example 1. Potassium chloride release from these systemswas monitored conductiometrically at 37° C. in a commercial AppliedAnalytical standard dissolution apparatus under the various conditionsof stirring: (a) 100 rpm continuously; (b) 100 rpm intermittent with 0rpm; (c) and 0 rpm continuously. The potassium chloride release profilesof FIG. 3 kept their uniformity and configuration for a prolonged periodwithout stirring induced effects for osmotic systems MMP-10, MMP-25, andMMP-50.

EXAMPLE 5

A plurality of osmotic systems were manufactured according to theprocedure of Example 1, wherein the conditions were as described exceptthat the wall forming solution was applied for sufficient duration so asto produce osmotic systems with wall thicknesses of 0.016 cm, 0.029 cm,and 0.044 cm. Potassium chloride release from these osmotic systems wasmonitored according to the procedure of Example 1. The release profilesdepicted in FIG. 4 were continuous for a prolonged period with releaserates decreasing with increasing wall thickness. A plot of 1/(wallthickness) versus means release rate is given in FIG. 5 indicating thatthe osmotic release of potassium chloride is in accordance with theinverse proportionality: ##EQU3##

EXAMPLE 6

A plurality of osmotic systems were manufactured according to theprocedure of Example 1, wherein the conditions were as described.Release of potassium chloride from these osmotic systems into 200 mlvolumes of unstirred water, pH 1.2 HCl buffer, or pH 8 phosphate buffersolutions adjusted with sodium chloride to be isoosmotic with blood wasfollowed by conductiometrically analyzing the potassium chloride residuefrom 3 osmotic systems at each time interval by cutting the wall anddissolving the contents in distilled water. Based on an initial amountof 0.65 g KCl in the core composition, the amount of KCl released ateach time was calculated with equation 2. ##EQU4## The release profileis depicted in FIG. 6 where a clear indpendence of release rate from thepH of the external fluid is evident.

EXAMPLE 7

A plurality of osmotic systems were manufactured according to theprocedure of Example 1, wherein the conditions were as described.Release of potassium chloride from these osmotic systems into 200 mlvolumes of unstirred distilled water, 1.5 molar urea, 3 molar urea, 5.3molar urea, or 7.5 molar urea at 25° C. was followed byconduction-metrically analyzing the potassium chloride residue from 3osmotic systems at each timer interval by cutting the wall anddissolving the core composition contents in distilled water. The releaseprofiles are depicted in FIG. 7 where increasing the urea concentrationin the external fluid reduced the release rate of the potassium chloridefrom the osmotic system as evidenced by the diminishing slopes of thelines.

The osmotic pressures of the various fluids of concern were calculatedusing established thermodynamic relationships and experimental data asgiven in Electrolyte Solutions 2nd Revised Edition, by R. A. Robinsonand R. H. Stokes, pages 29-30, 1959, published by Butterworth and Co.Ltd., London; Aust. J. Chem., Vol. 20, pages 2087-2100; and J. Amer.Chem. Soc., Vol. 60, pages 3061-3070. The net osmotic pressuredifference that exists across the wall of the osmotic system wascalculated with Equation 3. ##EQU5## A plot of potassium chloriderelease rate versus π_(net) is given in FIG. 8 to illustrate thedependence of core composition release rate on the osmotic pressuredifference across a wall barrier permeable to both an external fluid andcore composition.

EXAMPLE 8

A plurality of osmotic systems for the osmotically-controlled release ofthe beneficial drug sodium indomethacin trihydrate were made as follows:First, 3 g sodium indomethacin trihydrate were mixed with 4.5 g sorbitolin a commercial Mini Mill for 1 minute. 250 mg aliquots wereindividually weighed and compressed in a standard 3/8 inch extra deepconcave tableting die under 3 tons pressure on a Carver hydraulic pressto form the core composition masses of the invention. 30 Such coremasses were manufactured. The solution utilized to form the controlledporosity wall was prepared according to the procedure of Example 1,wherein the conditions were as described, except that the sorbitolcontent of the wall forming solution was 9 g. Next, 30 core compositionmasses were mixed with 700 g of potassium chloride placebo tablets in acommercial Uni-Glatt fluidized bed machine, wherein the wall formingsolution was applied to the core masses until a thickness of 95 micronswas attained. The finished osmotic systems were dried in an oven to 50°C. to facilitate removal of residual solvents.

The release of sodium indomethacin from these osmotic systems into 0.07Mphosphate buffer, pH 6.6, was monitored by ultraviolet light absorptionmeasurements at a wavelength of 320 nm in standard 1 cm pathlengthquartz cells in a commercial double beam Beckman Acta Vspectrophotometer. Release was conducted at 37° C. with 100 rpm stirringprovided by paddles in a commercial Applied Analytical standarddissolution apparatus. The release profile is depicted in FIG. 9 wherethe equivalent mgs of indomethacin in free acid form released versustime in hours is plotted. The release was continuous and uniform for aprolonged period at a mean rate of 34.6 mg/hr.

EXAMPLE 9

A plurality of osmotic systems for the osmotically-controlled release ofthe beneficial drug sodium indomethacin trihydrate were made as follows:First, 3 g sodium indomethacin trihydrate was mixed with 13.5 g sorbitolin a commercial Mini-Mill for 1 minute. 550 Mg aliquots wereindividually weighed and compressed in a standard 3/8 inch extra deepconcave tableting die under 3 tons pressure on a Carver hydraulic pressto from the core composition masses of the invention. 30 Such coremasses were manufactured. The wall forming solution was preparedaccording to the procedure of Example 8, wherein the conditions are asdescribed except that the sorbitol content of the wall forming solutionwas 3.6 g. Next, 30 core composition masses were mixed with 700 g ofpotassium chloride placebo tablets in a commercial Uni-Glatt fluidizedbed machine, wherein the wall forming solution was applied to the coremasses until a thickness of 130 microns was attained. The finishedosmotic systems were dried in an oven at 50° C. to facilitate removal ofresidual solvents.

The release of sodium indomethacin from these osmotic systems into 0.07Mphosphate buffer, pH 7.4, made isoosmotic to blood with additionalsodium chloride was monitored by ultraviolet light absorptionmeasurements at a wavelength of 320 nm in standard 1 cm pathlengthquartz cells in a commercial Beckman DU-7U spectrophotometer. Releasewas conducted at 37° C. with 100 rpm stirring provided by paddles in acommercial Applied Analytical dissolution apparatus. The release profileis depicted in FIG. 10 where the mgs of sodium indomethacine trihydratereleased versus time in hours is plotted. The release was continuous anduniform for a prolonged period at a mean rate of 20.7 mg/hr of sodiumindomethacin trihydrate.

EXAMPLE 10

A plurality of osmotic systems for the osmotically controlled release ofthe beneficial drug cyclobenzaprine HCl were made as follows: First, 3.7g cyclobenzaprine HCl were mixed with 60 g α-D-glucose and 17.5 gdistilled water to form a mass that was forced through a No. 12 screenand dried in vacuo at 50° C. for 24 hours to constitute granules fordirect compression. Aliquots containing 29 mg cyclobenzaprine HCl wereindividually weighed and compressed in a standard 7/16 inch tabletingdie under 4 tons pressure to form core composition masses of theinvention. 14 Such masses were manufactured. The wall forming solutionwas prepared according to the procedure of Example 8, wherein theconditions were as described. Next, 14 core composition masses weremixed with 700 g of potassium chloride placebo tablets in a commercialUni-Glatt fluidized fed machine, wherein the wall forming solution wasapplied to the core masses until a thickness of 110 microns wasattained.

The release of cyclobenzaprine HCl from these osmotic systems intodistilled water was monitored by ultraviolet light absorptionmeasurements at a wavelength of 290 nm in standard 1 cm pathlengthquartz cells in a commercial Beckman DU-7U spectrophotometer. Releasewas conducted at 37° C. with 100 rpm stirring provided by paddles in acommercial Applied Analytical standard dissolution apparatus. Therelease profile is depicted in FIG. 11 where the mgs of cyclobenzaprineHCl released was continuous and uniform for a prolonged period at a meanrate of 6.9 mg/hr. The total amount released in a zero-order fashion wasapproximately 18 mg which agrees well with the theoretically anticipatedamount based on the solubility and density of the major osmotic agent inthe core composition as calculated from Equation 4: ##EQU6## In thisexample glucose was the major osmotic agent with a solubility to densityratio of 0.38 that calculates to 17.9 mg cyclobenzaprine HCl released inzero-order fashion.

EXAMPLE 11

A plurality of osmotic systems for the osmotically controlled release ofthe beneficial drug cyclobenzaprine HCl were made according to theprocedure of Example 10, wherein the conditions were as described exceptthat the core masses contain 25 mgs cyclobenzaprine HCl and the wallapplied to a final thickness of 260 microns.

The release of cyclobenzaprine HCl from these osmotic systems into 0.07Mphosphate buffers, pH 5 and pH 8, and HCl buffer pH 1 was monitored byultraviolet light absorption measurements at a wavelength of 290 nm instandard 1 cm pathlength quartz cells in a commercial Beckman DU-7Uspectrophotometer. Release was conducted at 37° C. with 100 rpm stirringprovided by paddles in a commercial Applied Analytical dissolutionapparatus. The release profiles are depicted in FIG. 12 wherecyclobenzaprine HCl release was uniform and continuous at all pH'sexamined for a prolonged period with zero-order release kineticsobserved for delivery of 15.5 mgs which is the theoretically anticipatedvalue based on the solubility and density of the major osmotic agent,glucose. The mean release rates at pH 1, pH 5, and pH 8 were 1.80 mg/hr,2.14 mg/hr, and 1/65 mg/hr respectively.

Cyclobenzaprine HCl has a pKa of about 8.5 and would be anticipated tohave a reduction in solubility as the pH increases. Analysis of fluidwithin the core of osmotic systems indicated that the pH within the corewas not the same as the pH in the external fluid, and thatcyclobenzaprine HCl was present in a dissolved state within the corefluids. The observed insensitivity of cyclobenzaprine HCl release toexternal fluid pH suggests that the intrinsic solubility ofcyclobenzaprine is not exceeded in the examples given and the releaserate is determined principally by the solubility behavior of the glucosecomponent in the core.

EXAMPLE 12

A plurality of osmotic systems for the osmotically-controlled release ofthe beneficial drug potassium chloride were made as follows: First, 0.78g aliquots of potassium chloride were compressed to a hardness of 15 kgby standard compression techniques in a Stokes tableting machine fittedwith a 3/8 inch extra deep concave punch. A total of 2 kg of suchtablets were prepared as osmotic core composition masses of theinvention. Next, 50 g of commercial polymer Eudragit RS-100 were addedto methylene chloride with subsequent addition of methanol and highspeed mechanical stirring to complete the dissolution of the polymer. Tothis was added 11 g of polyethylene glycol 400. To this solution wasadded in dropwise fashion, with stirring, a second solution of water andmethanol containing 12.5 g of sorbitol, to constitute the solutionutilized to form the controlled porosity wall of the invention. Thefinal solution contained approximately 2.5%, by weight polymer in asolvent system of methylene chloride, methanol and water in theapproximate weight ratio of 15:10:1. Next, about 500 ml of the potassiumchloride tablet core masses were charged into a commercial FreundHi-Coater baffled pan coating machine wherein the wall forming solutionwas applied to the cores until a thickness of 120 microns was attained.Twenty-five of the tablets were removed at this point with the remaindercoated to a final thickness of 190 microns.

The release of potassium chloride from these osmotic systems intodistilled water was monitored conductiometrically at 37° C. in acommercial Applied Analytical standard dissolution apparatus providing100 rpm stirring. The release profiles are depicted in FIG. 13 and werecontinuous and uniform for prolonged periods and agreed with thetheoretical predictions of Equation 1, Example 1. The mean release ratesare 0.14 g/hr and 0.078 g/hr for the 120 micron and 190 micron wallthicknesses respectively with the rate inversely proportional to thewall thickness.

EXAMPLE 13

A plurality of osmotic systems for the osmotically-controlled release ofthe beneficial drug cyclobenzaprine HCl were made as follows: Corecomposition masses were manufactured according to the procedures ofExample 9, wherein the conditions were as described except that thecyclobenzaprine HCl content of each core was 26 mg. Next, 37.5 gEudragit RS 100 and 12.5 g Eudragit RL 100 (polymers) were added tomethylene chloride (solvent) with subsequent addition of methanol(solvent) and high speed mechanical stirring to complete the dissolutionof the polymer and give a polymer blend having a water permeabiltiyintermediate to that of the individual Eudragit components. To thissolution was added in dropwise fashion, with stirring, a second solutionof water and methanol containing 25 g of dissolved sorbitol, toconstitute the solution utilized to form the controlled porosity wall ofthe invention. The final solution contained approximately 2.5%, byweight, polymer in a solvent system of methylene chloride, methanol andwater in the approximate weight ratio of 15:10:1. Next, 30 corecomposition masses were mixed with 500 ml of placebo potassium chloridetablets in a commercial Freund Hi-Coater pan coating machine wherein thewall forming solution was applied to the cores until a thickness of 285microns was attained.

The release of cyclobenzaprine HCl from these osmotic systems into 0.07M.05 phosphate buffer, pH 7.4, made isoosmotic to blood with sodiumchloride, was monitored by ultraviolet light absorption mesurements at awavelength of 290 nm in standard 1 cm pathlength quartz cells in acommercial Beckman DU-7U spectrophotometer. Release was conducted at 37°C. with 100 rpm stirring provided by paddles in a commercial AppliedAnalytical dissolution apparatus. The release profile is depicted inFIG. 14 where cyclobenzaprine HCl release was uniform and continuous fora prolonged period with zero-order kinetics in effect for release ofapproximately 16 mg of drug which agreed closely with the theoreticallyanticipated amount of 16.1 mg calculated with Equation 4 of Example 10with the major osmotic agent, glucose, dominating.

EXAMPLE 14 Performance of Multiple Osmotic Pump Elements in CarrierMedia

Multiparticulate osmotic systems for the controlled release of thebeneficial drug potassium chloride were made as follows: First, 45 mgaliquots of commercial reagent grade potassium chloride were compressedby standard compression techniques in a Stokes tableting machine fittedwith a 1/8 inch concave punch. A total of 1500 g of such particles wereprepared as core masses of the invention. The wall forming solution wasprepared according to the procedure of Example 1, wherein the conditionswere as described except that the sorbitol content was 9 g. Next, 500 gof the core particles were charged into a commercial Uni-Glatt fluidizedbed machine wherein the wall forming solution was applied to the coresuntil a thickness of 0.015 cm was attained. These particulate osmoticsystems served as the multiparticulate components of the finishedcomposition osmotic system. The particulate osmotic systems thusprepared were then utilized to deliver potassium chloride whenadministered as either a single particle, or a multiplicity ofparticles, to give the desired dose and rate of drug delivery. As amatter of convenience multiparticulates are commonly loaded into gelatincapsules for administration. The gelatin capsule serves as a solidcarrier medium for the osmotic pump elements. The gelatin is disruptedin the test medium, releasing the osmotic pump elements which thenrelease KCl.

The release of potassium chloride from multiparticulate osmotic systemsinto 12 one liter aliquots of distilled water receptor media wasmonitored conductiometrically at 37° C. in a commercial VanKel standarddissolution apparatus providing 100 rpm stirring with paddles. Each ofsix receptor media were charged with 1 No. 00 gelatin capsule containing15 particulate osmotic devices. The remaining 6 receptor media werecharged with 15 particulate osmotic devices without the aid of a gelatincapsule. The release profiles are depicted in FIG. 15. The release rateswith and without gelatin capsules were 0.274 g/hr and 0.278 g/hrrespectively, which suggested the steady state release rate wasindependent of the gelatin capsule. The lag time was approximately 8minutes longer with the gelatin capsule systems reflecting the timerequired for water to penetrate and disrupt the gelatin before osmoticdelivery of agent could begin. The theoretically anticipated release of0.56 g of KCl with zero-order kinetics was observed. The release ratesfor these multiparticulate systems were within 7% of the release ratesobserved with a single large osmotic system having a similar wall(Example 2) when the rates were normalized for wall thickness andsurface area differences. This indicated that the mechanism of osmoticdelivery did not change with the size reduction to small particles. Thepresent embodiment of multiparticulate osmotic pump elements in a solidhollow medium (gelatin capsule) that becomes disrupted in theenvironment of use is illustrated in FIG. 18b.

EXAMPLE 15 Characteristics of Isolated Controlled Porosity Walls

Transmembrane flux of water was measured at 37° C. in a jacketed glassosmosis cell having two compartments of equal volume (185 ml) separatedby a 14.34 cm² water equilibrated membrane sheet. Each compartment wasstirred continuously at 600 rpm with internally driven magnetic stirbars positioned immediately adjacent to the membrane. Initially, onechamber was filled with deionized water. The second chamber was filledwith a saturated aqueous solution of potassium chloride containingexcess solid and fitted with a capillary tube 35 cm long with an 0.5 mmdiameter core. The capillary was gravimetrically calibrated for volumeusing deionized water. The osmotically driven volume flux of water,dV/dt, from the first chamber into the second was measured by followingthe rise of fluid in the capillary with a cathetometer accurate to 0.01cm. The diffusive flux of potassium chloride from the second chamberinto the first chamber was measured conductiome- trically under the sameconditions as the water flux measurements except that the capillary waseliminated. Fluid levels in both chambers were kept equal throughout thediffusion experiments to eliminate hydrostatic pressure effects.

The membranes examined were identical in composition to walls applied tocore tablets in Examples 1, 2 and 3 and were prepared by spraying onto aflat glass substrate. The measured volume flux of water, dV/dt, ofEquation 1, for each membrane was multiplied by the potassium chloridesolubility, S=0.343 g/cm³, and normalized to a wall thickness of 0.016cm and area of 2.67 cm² to correspond to the wall dimensions of thedevices in Examples 1, 2 and 3. This was the calculated osmotic pumpcontribution to the total release.

The diffusive contribution, (dM/dt)_(D), was measured directly andnormalized to a wall thickness of 0.016 cm and area of 2.67 cm². The sumof the normalized osmotic pump and diffusive contributions was thecalculated total release rate anticipated for devices similar to thoseof Examples 1, 2 and 3. These values were compared to the actualobserved performance of the devices in FIG. 16. The calculated ratesagreed with the actual rates, with osmotic pumping the dominantcontribution in all cases. The fracitonal contribution of osmoticpumping increased as the weight percentage of pore former in the filmsincreased, while the diffusional contribution reached a constant value.

In all cases the walls were highly permeable to both water and salt. Theagreement between the calculated rates and the actual rates indicatedthat the walls had a low level of selectivity between water and saltflux. The reflection coefficient, σ, is an established indicator ofmembrane selectivity and has been defined in Biochimica et BiophysicaActa, Vol. 27, page 236, such that σ=0 for a totally non-selectivemembrane and σ=1 for a totally selective membrane that is permeable tosolvent (water) only. The low selectivity observed clearly indicatedthat σ was less than one. The data of FIG. 16 were consistent with σvalues less than 0.5. In fact, the σ value for MMP-50 was determined tobe 8.55×10⁻⁴ and the σ value for MMP-25 and MMP-10 estimated at lessthan 0.1.

EXAMPLE 16

Sections of the walls from devices described in Example 2 wereequilibrated in deionized water for 8 hours to leach out the watersoluble pore forming additives. These samples were critical point driedwith carbon dioxide by standard methods and viewed with a scanningelectron microscope. A typical micrograph is presented in FIG. 17. Thewalls were sponge-like in appearance with a distribution of pores thatwere less than 100 microns in diameter.

What is claimed is:
 1. A multiparticulate osmotic pump, for thecontrolled release of a pharmaceutically active agent to an environmentof use, said pump comprising:(I) a carrier medium which does notmaintain its integrity in the environment of use; (II) a multiple oftiny osmotic pump elements each consisting essentially of:(A) a corecomprises at least one pharmacologically active agent soluble in anexternal fluid, or a mixture of an agent having a limited solubility inthe external fluid with an osmotically effective solute that is solublein the fluid, which exhibit an osmotic pressure gradient across the wallagainst the external fluid surrounded by (B) a rate controlling waterinsoluble wall, having a fluid permeability of 6.96×10⁻¹⁸ to 6.96×10⁻¹⁴cm³ sec/g and a reflection coefficient of less than 0.5, prepared from:(i) a polymer permeable to water but impermeable to solute and (ii) 0.1to 60% by weight, based on the total weight of (i) and (ii), of at leastone pH insensitive pore forming additive dispersed throughout said wall.2. The osmotic pump of claim 1, wherein said pore forming additivecomprises:(a) 0.1 to 50%, by weight, solid additive, based on the totalweight of (i) and (ii), and/or (b) 0.1 to 40%, by weight, liquidadditive, based on the total weight of (i) and (ii), not to exceed atotal weight % of pore forming additive of 60%.
 3. The osmotic pump ofclaim 1, wherein said reflection coefficient is less than 0.1.
 4. Theosmotic pump of claim 1, further comprising:(C) 0 to 50 parts per 100parts of (i) and (ii) of plasticizer and flux regulating additives and(D) 0 to 40 parts per 100 parts of (i) and (ii), of surfactant additive.5. The osmotic pump of claim 1, wherein said water insolube wall is 1 to1,000 microns thick and wherein 5 to 95% of the resulting wall pores arebetween 10 angstroms and 100 microns in diameter.
 6. The osmotic pump ofclaim 5 wherein said wall is 20 to 500 microns thick and said wall poresare between 10 angstroms and 25 microns in diameter.
 7. The osmotic pumpof claim 1, wherein at least 0.05 ng of active agent are used.
 8. Theosmotic pump of claim 7, wherein at lest 1 microgram of active agent isused.
 9. The osmotic pump of claim 1, wherein said polymer is selectedfrom the group consisting of cellulose esters, acryaltedpolysaccharides, polyurethane, polymers of acrylic and methacrylic acidand esters thereof, poly (ortho ester)s, polyacetals and mixturesthereof.
 10. The osmotic pump of claim 9, wherein said polymer isselected from the group consisting of cellulose esters and acylatedpolysaccharides.
 11. The osmotic pump of claim 9 wherein said polymer isselected from the group consisting of polyurethanes and polymers ofacrylic and methacrylic acid and esters thereof.
 12. The osmotic pump ofclaim 9, wherein said polymer is selected from the group consisting ofpoly(ortho ester)s and polyacetals.
 13. The osmotic pump of claim 1,wherein said pore forming additive is selected from the group consistingof water, alkali metal salts, alkaline earth metal salts, saccharides,aliphatic polyols, aromatic polyols and mixtures thereof.
 14. Theosmotic pump of claim 1, wherein 0.1 to 50%, by weight, of said poreforming additive is used.
 15. The osmotic pump of claim 1, wherein saidpH insensitive pore forming additive is selected from the groupconsisting of polyethylene glycol, sorbitol, glucose and mixturesthereof.
 16. The osmotic pump of claim 1, wherein said active agent isselected from the group consisting of potassium chloride, sodiumindomethacin trihydrate and cyclobenzaprine HCl.
 17. The osmotic pump ofclaim 1, wherein said active agent is selected from the group consistingof quinoline carboxylic acids, naphthyridine carboxylic acids,pyrimidine carboxylic acids, and cinnoline carboxylic acids.
 18. Theosmotic pump of claim 1 wherein the carrier medium is solid.
 19. Theosmotic pump of claim 18 wherein the solid carrier medium is a solublegelatin capsule or tablet matrix.
 20. The osmotic pump of claim 19wherein the solid carrier medium is a soluble gelatin capsule.